Early Life Seizures Differentially Activate c-Fos in Hippocampal CA1 Cell Populations

Issue: 
2021
Institution: 
University of Pennsylvania, Philadelphia, PA, 19104

Early life seizures (ELS) are quite different from those in adults and can be associated with longlasting deficits in cognitive and behavioral function. A majority of the epileptic syndromes that occur in childhood indicate that the developing brain has a great capability to generate seizures. The mechanisms of ELS include multiple molecular and cellular processes in the activitydependent subpopulation of neurons with the expression of immediate-early genes (IEGs, such as c-Fos). This present study used a transgenic mouse model, in which CreER and following tdTomato expression was driven by Fos promoter (FosTRAP1), to permanently label the ELSassociated cells in the CA1 region of the hippocampus. CreER is Cre recombinase to promote high-level expression. TdTomato is a red fluorescent protein to permanently label CreER recombination. We measured tdTomato expression in the hippocampus in brain sections from FosTRAP1 mice with and without seizures. The chemoconvulsant kainate (KA) induced seizures was associated with a statistically significant increase of c-Fos expression shown by permanent tdTomato fluorophore labeling. Video analysis determined that there was a statistically significant correlation between tonic-clonic seizure duration and c-Fos expression in FosTRAP1 mice. In immunohistochemistry (IHC) experiments, brain sections were stained with different neuronal markers (NeuN, Iba-2, GFAP, and GAD-67) to confirm cell identity. Image analysis revealed that the vast majority of stained cells were pyramidal neurons, based on colocalization of the NeuN labeled and tdTomato+ cells. IHC staining also determined there was minimal colocalization of tdTomato+ cells and neuronal markers in glial cells, astrocytes, and GABAergic inhibitory interneurons. Given the prevalence of intellectual disability and social deficits following seizures in early life, identification of cells activated by seizures will allow further studies to examine their structure and function after seizures, in order to identify new therapeutic targets for potential clinical use.

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